The overall goal of this research is to better understand the role of ocular lipofuscin in macular degeneration. In doing so we develop clinically relevant ways to inhibit lipofuscin formation (as possible interventions for macular degeneration) and develop animal models of lipofuscin-induced macular degeneration. The specific aims of this application are: AIM 1) elucidate the relationship between lipofuscin and retinal health and the mechanism of lipofuscin formation: a) determine whether slowing lipofuscin biosynthesis can prevent ocular aging and vision loss in rodent models of macular degeneration; b) determine whether increasing the concentration of vitamin A dimers in the RPE leads to the formation of lipofuscin granules and drusen; and c) determine whether animals models of macular degeneration can be generated by rapidly increasing lipofuscin pigments; and AIM 2) elucidate pharmacokinetics vitamin A and vitamin A dimers in the eye: a) determine the time it takes to swap vitamin A for D3-vitamin A in the outer segments; b) establish the RPE half life of vitamin A dimers; c) determine whether the rate of lipofuscin pigment biosynthesis increases with age or whether lipofuscin pigments themselves accumulate with age, and; d) compare visual cycle kinetics of vitamin A vs. D3-vitamin A. We will achieve these specific aims by slowing down or speeding up lipofuscin formation in animals, using novel methods developed in our lab, and correlating eye health to lipofuscin concentration. In evaluating eye health in response to changes in lipofuscin we employ standard methods such as, tissue histology, fundus autofluorescence, electroretinogram measurements, inflammatory status and quantification of vitamin A dimers. For the elucidation of the ocular pharmacokinetics of vitamin A and its dimers we track their fate and/or biosynthesis using deuterium or tritium labeled species. We intend to show that the biosynthesis of vitamin A dimers (also called or lipofuscin pigments or A2E and ATR-dimer) is an early and critical step in the formation of lipofuscin granules (or deposits) in the RPE cell layer of the eye; that lipofuscin granules lead to the formation of drusen (or drusen like material) and ultimately cell death and vision impairment. We intend to show that stopping the biosynthesis of vitamin A dimers is an effective clinical strategy to stopping the formation of lipofuscin and drusen, as a method to stop the progression of the most prevalent forms of macular degeneration. We intend to gather evidence to show that the administration of D3-vitamin A is a safe, practical, method to prevent the progression of several forms of macular degeneration. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to overall public health because it seeks ways to better understand and prevent macular degeneration.